Knee osteoarthritis (OA) is the leading cause of lower extremity disability among older adults in the United States. Knee replacement (KR) is the only definitive treatment available for knee OA presently. Reflecting this, ~0.5 million KRs were performed in 2004, with ~3.5 million projected by the year 2030. Despite replacement of the diseased joint, 20-30% of patients have inadequate pain relief from this presumably definitive major surgical procedure aimed at improving pain. The reason for suboptimal pain relief is not entirely clear. Central sensitization, which is an abnormal excitability of neurons in the central nervous system, causes heightened pain sensitivity and is therefore a plausible contributing factor to ongoing pain after KR. Central sensitization can occur for a variety of reasons, including inflammatory inputs from diseased tissue and other systemic sources (such as obesity, a major risk factor for OA, which is associated with low-grade inflammation), and the surgery itself. Preliminary pilot data support the cross-sectional relation of central sensitizatio to severe pain post-KR and radiographic knee OA, suggesting the possibility of OA pathology contributing to sensitization. The objective of this study is to comprehensively study the relation of: 1) central sensitization to pain post-KR; 2) the duration and severity inflammatory features of OA (synovitis, effusion) as well as inflammatory mediators that may act locally or systemically (TNF-, adiponectin, leptin) to central sensitization. These studies will provide insight into potential pathophysiologic mechanisms underlying post-KR and knee OA pain, and occurrence of central sensitization. The study will be conducted within the NIH-funded Multicenter Osteoarthritis (MOST) Study, which is a cohort of ~3000 older adults with knee OA of varying severity and duration as well as persons who are at high risk for knee OA, who have had longitudinal standardized assessments of disease, pain, and function over 7 years to date. This study will create a new post-KR cohort to enable greater assessments of central sensitization pre- and post-KR as these measures were not obtained in all those with KR previously, and will enable assessment of neuropathic pain as a contributor to post-KR pain. Two measures of central sensitization will be evaluated: 1) temporal summation and 2) pressure pain threshold, which is a marker of peripheral and/or central sensitization at sites of disease, or of central sensitization when assessed at an otherwise normal area. These evaluations will occur in the context of other pertinent factors associated with poor KR pain outcomes that are comprehensively collected in this cohort. Insight into the role of central sensitization in pain post-KR, and the inflammatory pathology of OA or other systemic inflammatory mediators that may contribute to central sensitization will offer opportunities to develop rational new targets fo improving pain outcomes in knee OA earlier in the disease process, as well as improving pain outcomes post-KR, which is currently the only definitive therapy available for knee OA. PUBLIC HEALTH RELEVANCE: Knee replacement surgery is the only definitive treatment available for osteoarthritis, the leading cause of lower extremity pain and disability among older adults in the United States, yet a substantial number of people continue to have pain after knee replacement. Accordingly, there is a vital need to understand what factors may explain why some people do not achieve adequate pain relief post-knee replacement, particularly since such a large number of such surgeries are performed in the United States. This research will provide important information regarding nervous system alterations (sensitization) as a potential risk factor for pain persistence post-knee replacement, and whether inflammation may contribute to these alterations, thereby increasing our understanding of potential causes of and treatment targets for pain in osteoarthritis and post-knee replacement.